PROJECT SUMMARY/ABSTRACT The primary aim of this proposal is to develop peptidomimetic and proteomimetic synthetic agents that can modulate protein-protein interactions (PPIs) and protein-membrane interactions (PMIs) of clinically significant targets. We will develop novel organic architectures to display amino acid side chain isosteres at a density and periodicity that mimics their biological counterparts. In particular, derivatives of the non-planar dipeptide mimetic meta-aminomethylbenzoic acid (MAMBA) will be pre-organized by directed hydrogen bond templation and evaluated as beta-sheet mimetics in linear and cyclic oligomer forms. Traditional drug discovery methods have largely failed when targets lack accessible active sites or deep ligand binding pockets. PPIs are characterized by large contact areas (often greater than 1000 angstrom^2) that confer binding strength and specificity through the sum of many weak forces. Aberrant or misregulated PPIs play a tremendous role in human disease states. Thus, small molecules and supramolecular assemblies capable of modulating PPIs present a complementary approach in drug discovery. It is estimated that over one-quarter of human proteins are membrane-associated and that membrane proteins comprise more than half of approved drug targets. Therefore, the interactions of membrane proteins with other proteins and with the cell membrane (PMIs) are of significant clinical interest. This application proposes the development of synthetic agents to study and manipulate PMIs of medically relevant targets. The oncogenic protein Ras, associated with over one-third of human cancers, is an ideal case study for synthetic compounds that target PPIs and PMIs. Ras GTPases bind their substrate nucleotides with picomolar affinity and possess scant ligand binding pockets. They have therefore been deemed ?undruggable? by traditional medicinal chemistry methods. This research proposes to develop synthetic agents targeting Ras PPIs. Because Ras is membrane-tethered by posttranslational prenylation, we will also investigate compounds that target Ras PMIs in model membrane systems. The development of synthetic regulators of PPIs and PMIs in general is of great clinical interest and the targeting of oncogenic Ras in particular is of high medical priority.